Production of chemical compounds



United States Patent D PRODUCTION OF CHEMICAL COMPOUNDS Basil JasonHeywood, Dagenham, England, assignor, by

mesne assignments, to Parke,Davis & Company, Deqtroit, Mich., acorporation of Michigan No Drawing. Originalapplication November 16,1951,

Serial No. 256,821. Divided and this application February 23, 1956,'Serial No. 569,666

r 4 Claims. "(CL 260-466) compounds can be prepared by the hydrolysis ofthreo 2-substituted-4-hydroxymethyl (or acyloxymethyl)--p-nitrophenyl-a-oxazolines. Convenient starting materials for the preparation'of theseoxazolines are the corresponding erythro (otherwise known as allo) formsof 2- acylamido-l-p-nitrophenylpropane 1:3-dials and the process thenhas involved at one stage or another the step of 'epimerisation.

As a result-of research in connection with the aforesaid process, thepresent applicants have now discovered that the desired threo oxazolinesof the general formula:

can readily be obtained, uncontaminated to any substantial extent witherythro epimer, if the erythro Z-acylamidol-p-nitr-ophenylpropane1:3-diols are first converted into derivatives of the type:

ONO: -NHCOR1 In these formulae R represents an acyl or carboalkoxygroup, COR represents an aliphatic acyl group containing not more than 4carbon atoms, preferably acetyl or halogen-substituted acetyl, and Rrepresents either a hydrogen atom or the group R.

The process of the present invention consists in reacting the nitricester ofgeneral Formula II with alkali (preferably sodium hydroxide),preferably in the cold or at moderate temperature (i. e. at atemperature not in excess of about 40 C.) and preferably inan organicsolvent such as aqueous ethyl alcohol.

When the radical R is a readily hydrolysable group such as acetyl,benzoyl, acid succinyl or carbethoxy, it will be hydrolysed under theconditions of reaction of the nitric ester of Formula II with alkali, inwhich event the product of the reaction is a 4-hydroxymethyl oxazoline.Where, however, a more stable group R is employed the reaction productis a 4-acyloxymethyl or 4-carboalkoxyoxymethyl oxazoline, the acyl orcarboalkoxy group of which is eitherrernoved during the subsequent stageof hydrolysis, in known'mannen'of the'oxazoline or subseice quentthereto. It is, of course, possible to choose the COR, and R groups suchthat the conditions for hydrolysis of the R group will ensure hydrolysisalso of the COR group and, if such conditions are applied .to hydrolysisof the oxaz oline or to the resultant product of hydrolysis, theultimate product is the threo 2amino-1 -pnitrophenylpropane 1:3-diolinsteadof the corresponding Z-acylarnido compound.

I Since an important feature of the present invention is to provide anoxazoline which is directly convertible by hydrolysis intochloramphenicol or the DL-mixture of which it is the D- compound, it ispreferred that the radical R shall be dichloromethyl and R be a readilyhydrolysable group, in which event the reaction may be representedschematically as follows:

OzN

(erythro) lalkall OzNC (|3H(|3H-CH2OH (threo) According to a preferredfeature of the invention, -DL- or L-erythro2-clichloroacetamino-3-acetoxy-l-p-nitrophenylpropane l-ol is treatedwith concentrated nitric acid (s. g. 1.50) and an alcoholic solution orsuspension of the resultant nirtic ester is treated with a slight excessof s'odium or potassium hydroxide solution at room temperature or at amoderate temperature (i. e. a temperature not exceeding about 40 C.) toform DL- or D-threo Z-dichloromethyl 4 hydroxymethyl 5 p nitrophenyl h-oxazoline.

A particular advantage of the present invention is that the preferredoxazolines, namely DL and D(-) threo 2- dichloromethyl 4 hydroxymethyl 5p nitrophenyl h -oxazolines can be obtained directly ina pure. state.uncontaminated by any of the other isomericZ-Idichloromethyl-4-p-nitrophenyl-hydroxymethyl-A -oxazolines vand assuch can be converted (by dissolving in dilute mineral acid followed byneutralisation with a base) into DL- or D-threoZ-dichloroacetamido-l-p-nitrophenylpropane .1 3- diol. The full processcan then be regarded as a process for the inversion of erythro2-dichloroacetamido-1 p-nitrophenylpropane 1 :3-diols.

The present invention is illustrated by the following examples:

Example 1 DL-erythro 2-dichloroacetamido-3-acetoxy-l-pnitrophenylpropane l-ol (1.0 g.) was added to stirred nitric acid (4.0cc.; s. g. 1.50), cooled to C. The stirred pale yellow nitric acidsolution was allowed to warm spontaneously to 0 C. over about one hour.The solution was then poured into a stirred mixture of water (25 cc.)and ice (25 g.) and the suspension so obtained stirred for 15 minutes.The white solid was filtered off, powdered in a mortar, and washed withwater. The yield of crude nitric ester was almost quantitative.Crystallization of the crude product from methanol (15 cc.) gave pureDL- erythro 2-dichloroacetamido-3-acet0xy-l-p-nitrophenylpropane l-olnitric ester in pale yellow cubes, M. P. 126-7 C. The yield was 0.80 g.or 71.5% of theory. 0

The DL-erythro 2-dichloroacetamido-3-acetoxy-l-pnitrophenylpropane 1-olwas obtained by reacting'DL- erythro 2-dichloroacetamido-l pnitrophenylpropane 3- die! with slightly over the theoretical quantityof acetyl chloride in the presence of pyridine. The product melts at116-7 C.

The DL-erythro 2-dichloracetamido-3-acetoxy-l-p-nitrophenylpropane l-olnitric ester (410 mg), as prepared above, was suspended in methanol (8cc.) at C. To the stirred suspension was added slowly 2N sodiumhydroxide solution (1 co.). After three minutes a pale yellow solutionwas attained and the solution was then gradually heated to 3040 C. Aftermaintaining at this temperature for 10 minutes, the reaction mixture wascooled to 10 C. and neutralized with 2N acetic acid solution. Theproduct crystallised out, on adding distilled water, as pale yellowplates. Crystallisation of the product from aqueous methanol gave pureDL-threo 2- dichlorornethyl-4- hydroxymethyl-S-pnitrophenyl-n-oxaz'oline, M. P. 1289 C.

I If the crude DL-erythro2-dichloracetamido-3-acetoxyl-p-nitrophenylpropane l-ol be converteddirectly to the oxazoline, the overallyield then is 80% of thetheoretical yield.

Example II L-erythro 2- dichloracetamido-3- acetoxy-lpnitrophenylpropane1-01 (1.35 g.) was added evenly to stirred nitric acid (s. g. 1.50)cooled to about 30 C. The reaction mixture was allowed to warmspontaneously to 0 C. and the clear colourless solution so obtainedpoured onto a stirred ice-water mixture (20 g.). The whitemicro-crystalline suspension was stirred for 10 minutes prior tofiltering off and water-washing the crude L- erythro 2-dichloracetamido- 3- acetoxy-l-pnitrophenylpropane l-ol l-nitric ester.The yield of this material was 90% of theory (1.35 g.) and the meltingpoint of the material after crystallisation from methanol was 139-40 C.

' Crude L-erythro Z-dichloroacetamido-S-acetoxy-l-pnitrophenylpropane1-01 (2.0 g.) was suspended in methanol (10 cc.) and then a slightexcess of 2N sodium hydroxide added. At first a yellow solution wasobtained, but later crystals separated out. After standing at laboratorytemperature for three-quarters of an hour and then .at 35 C. for 10minutes, the suspension was cooled to C. prior to filtering oil the paleyellow crystals. The D-threo 2-dichloromethyl-4-hydroxymethyl-S-p-nitrophenyl-A -oxazoline (1.15 g.) was obtained in a77.5% of theory yield and the product meltde at 1335 C.

The overall yield for the two stages was 70% of theory.

Example III DL-erythro 2- dichloracetamido-3-benzoxy-1-pnitrophenylpropane 1-ol (0.96 g.) was added evenly to stirrednitric acid (s. g. 1.50 at about -30 C. over five minutes. During thecourse of one hour the pale yellow solution was allowed to warmspontaneously to 0 C. The solution was poured onto a stirred mixture ofwater (25 cc.) and ice (25 cc.). After stirring for 1.5 minutes, thewhite suspension was filtered and the solid washed well with wateranddried in a vacuum desiccator. The yield (1.10 g.) was.95% sincedinitration had occurred and the productwas therefore, DL-erythro2-dichloracetamido-3-mnitrobenzoxy-l-p-nitrophenylpropane l-ol l-nitricester. The melting point of the product after crystallisation frommethanol was 138.8 to 141.5 C.

DL-erythro 2-dichloracetamido-3-m'-nitrobenzoxy-l-pnitrophenylpropanel-ol 1-nitric ester (0.6 g.) was suspended in stirred methanol (12 cc.)at 0 C. and 2N sodium hydroxide (1.5 cc.) was added to give a paleyellow solution. The reaction mixture was then heated to 30-40 C. andheld atthis temperature for minutes. The solution was cooled to 10 C.prior to precipitating out the oxazoline by the addition of distilledwater. The yield of crystals (0.23 g.) was 64% of theory. The crudeDL-threo 2-dichloromethyl-4-hydroxymethyl-5-pnitropheny'l-A oxazolinemelted at 127-1285 C.

4 Example IV C. for 10 minutes and then cooled to 10 C. The productcrystallised out on addition of distilled water. The yield of crudeDL-threo 2-dichloromethyl-4-hydroxymethyl-5- p-nitrophenyl-A -oxazolinewas 60% of theory and it melted at 123.5128 C.

Example V DL- erythro 2- dichloracetamido-3-succinoxy-l-p-nitrophenylpropane l-ol (2 g.) was converted to thel-nitric ester in a similar way to that described in the precedingexamples. The crude nitric ester, which was not obtained crystalline,was converted directly to the oxazoline by treatment of a methanolicsolution at 30-40 C. with 2N sodium hydroxide which was added dropwiseat such a rate that the reaction medium was always just alkaline toClayton Yellow test paper. The reaction mixture was maintained for 10minutes at 3040 C. after the last addition of sodium hydroxide and thencooled to 10 C. The oxazoline was isolated in the same way as describedin the preceding examples.

Example VI DL-erythro 2-dichloracetamido3-acetoxy-1-p-nitrophenylpropane 1-ol nitric ester (410 mg. as prepared in Example I) wassuspended in methanol (8.0 cc.) at 0 C. while 2N potassium hydroxide 1.5cc.) was added gradually. The reaction mixture was allowed to stand forone hour at 0 C. and then heated to 30-40" C. for 10 minutes. Theproduct was isolated by first cooling the reaction mixture to 10 C. andthen by adding distilled water. The DL-threo2-dichloromethyl-4-hydroxymethyl-5-p-nitrophenyl-A -oxazoline (210 mg,M. P. l278 C.) was obtained in a 76% of theory yield.

I claim:

1. Process which comprises mixing a compound of formula OH NHCORi withconcentrated nitric acid at a temperature below about 0 C. therebyproducing a compound of the formula ONO I Nor-Oon-oH-omoR where R is amember of the class consisting of carboxylic acid acyl and carboalkoxygroups and R is a member of the class consisting of methyl and halogensubstituted where R is a member of the class consisting of carboxylicacid acyl and carboalkoxy groups and R is a member of the classconsisting of methyl and halogen substituted r'nethyl'groups.

3. Process which comprises mixing an erythro acylamido compound offormula ONO: 10

4. A compound having the formula ONO:

NHCO-CHCh References Cited in the file of this patent FOREIGN PATENTSBelgium Sept. 15, 1951 Great Britain June 23, 1954

1. PROCESS WHICH COMPRISES MIXING A COMPOUND OF FORMULA